Epidemiological studies suggest an inverse association between the intake of whole-grain cereal food and the risk of pancreatic cancer, one of the deadliest malignancies. However, it remains unclear whether a specific bioactive component of cereal food can be used to modify the pancreatic cancer process. Tocotrienols, the predominant vitamin E compounds in cereal foods, have been proposed as potential anticancer agents due to their clinical safety as well as their chemopreventive activity and inhibitory effects on cancer cells in experimental models. We have observed that 4-tocotrienol inhibits the growth and survival of pancreatic cancer cells in vitro and in vivo. Our preliminary study also shows accumulation of bioactive concentrations of 4-tocotrienol in the pancreatic tissue of mice following oral administration. These findings combined with its superior efficacy and safety, make 4-tocotrienol a promising anticancer bioactive component of cereal food and constitute a compelling argument to study its mechanism of action in pancreatic oncogenesis. We propose to test two hypotheses: a) that 4-tocotrienol is a chemopreventive micronutrient against pancreatic cancer, and b) that 4-tocotrienol inhibits the effectors of oncogenic Ras signal transduction pathways in the pancreas and that this effect accounts for its antitumor activity. Oncogenic Ras activation is a key event in pancreatic carcinogenesis. Our preliminary data indicate that 4- tocotrienol strongly inhibits several effectors of activated Ras in pancreatic cancer cells such as down regulation of the Mek/Erk and PI3K/Akt mitogenic and tumor survival signaling pathways and up regulation of p27. Our specific aims are: 1) To determine in the PDX-1-Cre;LSL-KRASG12D genetically engineered model of pancreatic cancer the efficacy of 4-tocotrienol against pancreatic carcinogenesis and elucidate its in vivo effect on Mek/Erk and PI3K/Akt signaling pathways. Specifically, we will determine the incidence and progression of pancreatic intraepithelial neoplasias; inhibition of Mek/Erk and PI3K/Akt activation; effects on cell proliferation, apoptosis, and relevant Mek/Erk and PI3K/Akt dependent genes that mediate this effect. 2) To elucidate the mechanistic basis for 4-tocotrienol induction of p27. Exportin-dependent nuclear export is linked to the degradation of p27, an important regulator of cell cycle progression in pancreatic cancer cells. Our preliminary data indicates that 4-tocotrienol binds to exportin and induces accumulation of p27 in pancreatic cancer cells. We will determine whether p27 is regulated by 4-tocotrienol/exportin binding. 3) To perform a phase 1 a/b trial to investigate whether consumption of 4-tocotrienol for 2 weeks prior to pancreatectomy will induce p27 and alter Mek/Erk and PI3K/Akt signaling pathways leading to an inhibition of proliferation and increase in apoptosis in the pancreas. Results of the proposed research will provide significant insight into the utilization of dietary tocotrienol in the prevention and therapy of pancreatic cancer. PUBLIC HEALTH RELEVANCE The objective of this project is to translate novel laboratory discoveries about the bioactive food component, delta-tocotrienol, to the prevention and treatment of pancreatic cancer, one of the deadliest malignancies known to man. Numerous epidemiological studies have indicated that consumption of whole-grain cereal foods reduce the risk of pancreatic cancer. However, it remains unclear whether a specific bioactive component of cereal food can be used to prevent the pancreatic cancer process. Tocotrienols, the predominant vitamin E compounds in cereal foods, have been proposed as potential anticancer agents due to their safety as well as their protective activity against cancer cells in experimental models. We have observed that 4- tocotrienol inhibits the growth and survival of pancreatic cancer cells by blocking some of the important signals triggered by the Ras oncogene which is the key oncogene that is implicated in the development of >90% of pancreatic cancers. These findings combined with its superior efficacy and safety, make 4-tocotrienol a promising anticancer bioactive component of cereal food and constitute a compelling argument to investigate its action in pancreatic tumor development. We propose to test the hypotheses that 4-tocotrienol is a protective micronutrient against pancreatic cancer by inhibiting the effectors of Ras signaling pathways. Specifically, we plan to determine 4-tocotrienol efficacy in the Ras genetically engineered model of pancreatic cancer. We have discovered that 4- tocotrienol binds to some novel proteins with important function in regulating the growth signals in cells. We plan to conduct detailed studies to understand how these tocotrienol binding proteins contribute to the bioactivity of tocotrienols against cancer cells. Finally, we will conduct a hypothesis driven phase 1 a/b trial to investigate whether consumption of 4-tocotrienol for 2 weeks prior to pancreatectomy will alter ras signaling pathways leading to an inhibition of proliferation and increase in apoptosis in human pancreatic tumors. The results from these studies will advance our understanding of how a bioactive food component such as delta-tocotrienol can be exploited for the prevention and treatment of pancreatic cancer.